Comparing the Quality and Predictiveness between 3D QSAR Models Obtained from Manual and Automated Alignment

Abstract

A set of 113 flexible cyclic urea inhibitors of human immunodeficiency virus protease (HIV-1 PR) was used to compare the quality and predictive power of CoMFA and CoMSIA models for manually or automatically aligned inhibitor set. Inhibitors that were aligned automatically with molecular docking were in agreement with information obtained from existing X-ray structures. Both alignment methods produced statistically significant CoMFA and CoMSIA models, with the best q(2) value being 0.649 and the best predictive r(2) being 0.754. The manual alignment gave statistically higher values, whereas the automated alignment gave more robust models for predicting the activities of an external inhibitor set. Both models utilized similar amino acids in the HIV-1 PR active site, supporting the idea that hydrogen bonds form between an inhibitor and the backbone carbonyl oxygens of Gly48 and Gly48' and also the backbone NH group of Asp30, Gly48, Asp29', and Gly48' of the enzyme. These results suggest that an automated inhibitor alignment can yield predictive 3D QSAR models that are well comparable to manual methods. Thus, an automated alignment method in creating 3D QSAR models is encouragable when a well-characterized structure of the target protein is available.

The Effect of Molecular Fields, Lattice Spacing and Analysis Options on CoMFA Predictive Ability

“…Both approaches resulted in equivalent statistical significance for every test and thus only the results of the LOO analyses are detailed below. Inhibitors of angiotensin converting enzyme 114 ACHE [11] Inhibitors of acetyl-cholinesterase 111 AI [25,29] Steroid aromatase inhibitors 78 ARB [30] Nonpeptide angiotensin II receptor antagonists 28 ATA [31] Anti-tuberculosis agents 94 BZR [11] Inhibitors of benzodiazepine receptor 163 CBRA [32] Cannabinoid CB1 receptor agonists 32 COMT [33] Inhibitors of catechol-O-methyltransferase 92 COX2 [11] Inhibitors of cyclooxygenase-2 322 DAT [34] Piperidine analogues for dopamine transporter 42 DHFR [11] Inhibitors of rat dihydrofolate reductase 397 DR [35,36] Antagonists of dopamine receptor 38 ECR [37] Binding of diacylhydrazine to ecdysone receptor 50 EDC [38] Estrogen disrupting chemicals 123 GHS [39] Growth hormone secretagogue mimics 31 GPB [11] Inhibitors of glycogen phosporylase b 66 GSK3B [40] Inhibition of Glycogen synthase kinase 3 42 HIVPR [41] Inhibitors of human immunodeficiency virus protease 113 HIVRT [42,43] Inhibition of HIV-1 reverse transcriptase 101 KOA [44] Kappa opioid antagonists 39 MX [45] Mutagenicity of mutagen X analogues 29 PDE [46] Inhibition of phosphodiesterase-IV 29 PTC [47] Phase-transfer asymmetric catalysts 40 RYR [25,48] Binding of ryanoids to the ryanodine receptor 18 STEROIDS [3,25] Binding of steroids to carrier proteins 21 TCHK [49] Inhibition of trypanosoma cruzi hexokinase 42 THERM [11] Inhibitors of thermolysin 76 THR [11] Inhibitors of thrombin 88 TP2A [50] Inhibition of topoisomerase-IIa 25 YOPH [51] Inhibitors of yersinia protein tyros...…”

Application of 3D-QSAR Techniques in Anti-HIV-1 Drug Design - An Overview

“…Tervo et al recently reported the comparison of quality and predictiveness between 3D-QSAR models obtained by manual and automated alignment methods [91]. A large series of 113 flexible cyclic urea based inhibitors divided into a training set consisting of 93 compounds were used to develop models by both the CoMFA and the CoMSIA techniques and a test set consisting of 20 compounds were used as an external set to validate the models.…”

QSAR Modeling of HIV‐1 Protease Inhibition on Six‐ and Seven‐membered Cyclic Ureas

“…Debnath also studied a larger set, a total of 118 cyclic ureas [15] and found models with R 2 up to 0.97, q 2 up to 0.73, and the validation sets R 2 up to 0.64. Later, Tervo et al [16] studied almost an equally large set using both CoMFA and CoMSIA approaches. The best models they found had R 2 up to 0.95, q 2 up to 0.65, and R 2 of the validation set up to 0.75.…”